Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis
Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis
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DOI：
10.1007/bf02256576
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发表时间：
2002-01-01
影响因子：
11
通讯作者：
Chiang, PK
中科院分区：
文献类型：
--
作者：
Zhang, P;Nicholson, DE;Chiang, PK
蛋氨酸氨肽酶 2 (MetAP2) 负责从大多数新合成的蛋白质中水解起始蛋氨酸分子。我们从疟原虫恶性疟原虫中克隆了 MetAP2 基因（PfMetAP2；GenBank 登录号 AF348320）。克隆的PfMetAP2无内含子，全长1,544 bp，编码354个氨基酸的蛋白质，分子量为40,537 D，总碱基组成为72.54% A+T。PfMetAP2与人MetAP2序列同一性为40%，与酵母MetAP2序列同一性为45%，位于恶性疟原虫14号染色体上。 Pf MetAP2 的三维结构是根据人 MetAP2 的晶体结构建模的，并且已鉴定出突出到结合口袋中的几个氨基酸侧链，这些氨基酸侧链在疟原虫酶和人酶之间有所不同。特定的 MetAP2 抑制剂夫马洁林和 TNP-470 在体外有效阻断恶性疟原虫和多纳瓦利什曼原虫的生长，其 IC50 值与原型药物相似。此外，就恶性疟原虫而言，氯喹抗性菌株对这两种化合物同样敏感。版权所有 (C) 2002 国家科学委员会、ROC 和巴塞尔 S. Karger AG。
Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC50 values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds. Copyright (C) 2002 National Science Council, ROC and S. Karger AG, Basel.